Dehydron as a Marker for Molecular Evolution: Lessons for the Drug Designer

Abstract

This chapter explores the significance of protein dehydron patterns as markers for molecular evolution. Since, as described in Chap. 4, dehydrons may be targeted by wrapping ligands that may eventually become therapeutic drugs, the evolutionary insights hereby obtained naturally have ramifications for the drug designer. Such ramifications will be exhaustively investigated in the remaining chapters of the book. Proteins with common ancestry (homologs) typically share a common fold, but this structural similarity introduces major problems for molecular targeted therapy since it may lead to hazardous off-target effects and prevent the control of specificity. As shown in this chapter, while the topology of the native fold is highly similar across homologs, the wrapping patterns tend to be different, enabling the wrapping drug to funnel its impact solely on clinically relevant targets. The evolutionary root of the differences in dehydron pattern across homologous proteins is dissected in this chapter both across species and within the human species. As first hinted in this chapter and further developed in the subsequent ones, wrapping variations across homologs can be exploited in drug design to considerable advantage as we aim at engineering target-specific and species-specific therapeutic agents and build meaningful animal models for disease and malignancy. In establishing the evolutionary forces that promote differences in the dehydron patterns across orthologous proteins, we discovered that random genetic drift plays an operational role in promoting dehydron enrichment. This type of structural degradation enhances the propensity for protein interactivity and becomes more pronounced in species with low population, such as humans, where the mildly deleterious mutations typically resulting from random drift have a higher probability of getting fixed in the population. The fitness consequences of this evolutionary strategy adopted by nature are assessed for humans, and reveal the high exposure of the human species to fitness catastrophes resulting from aberrant protein aggregation.